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PubMed1999

Identification of SEC12, SED4, truncated SEC16, and EKS1/HRD3 as multicopy suppressors of ts mutants of Sar1 GTPase.

The yeast SAR1 gene encodes a low-molecular-weight GTPase which is essential for the formation of transport vesicles from the endoplasmic reticulum (ER). To understand how the Sar1p function is regulated in its GTPase cycle, we searched for multicopy suppressors of sar1 temperature-sensitive mutants and identified SEC12, SED4, truncated SEC16, and EKS1. EKS1 turns out to be identical to HRD3, which was independently isolated as a gene implicated in the degradation of an HMG-CoA reductase isozyme, Hmg2p. In this paper, we show that the product of EKS1/HRD3 is a type-I transmembrane glycoprotein and resides in the ER. The eks1/hrd3 disrupted cells are normal in growth and transport of cargo proteins, but missecrete BiP (Kar2p). The overexpression of EKS1/HRD3, which stabilizes Hmg2p, did not affect the stability of wild-type or mutant Sar1p or any early Sec proteins we examined. These results suggest that the role of Eks1p/Hrd3p is not involved in the ER protein degradation in general but rather required for the maintenance of the ER membrane functions. The novel genetic interactions unveiled between SAR1, SEC12, SEC16, and SED4 will provide useful information as to how the complex machinery of vesicle budding operates.

Endoplasmic Reticulum↗
PubMed1986

Sar1-leu8-angiotensin II reverses the effects of captopril on renal function in rats.

In Inactin-anaesthetized rats inhibition of angiotensin converting enzyme by captopril resulted in a small decrease in mean arterial blood pressure accompanied by increases in the rates of glomerular filtration, water and electrolyte excretion. Infusion (100 pmol/min) of sar1-leu8-angiotensin II (sar1-leu8-AII) during continuing converting enzyme blockade reversed these changes in renal function but had no effect on arterial blood pressure. The data indicate that sar1-leu8-AII has partial agonist activity in the kidney although it acts as an antagonist of AII in the systemic circulation. This supports the proposal that angiotensin receptors within the kidney differ from those in the peripheral circulation.

Animals↗
PubMed1980

The effect of angiotensin II antagonist, Sar1-Ile8-angiotensin II, on furosemide-induced increase in plasma noradrenaline, renin activity and aldosterone in unanesthetized dogs.

In order to evaluate the role of the renin-angiotensin system and the sympathetic nervous system in the maintenance of blood pressure in the sodium-depleted state, the changes of plasma renin activity (PRA), plasma aldosterone concentration (PAC) and plasma noradrenaline (PNA) were examined in unanesthetized dogs after the administration of furosemide. Furthermore, the role of the renin-angiotensin system in the increased sympathetic nerve activity induced by furosemide was assessed by using Sar1-Ile8-angiotensin II, an angiotensin II antagonist. When a dose of 0.8 mg/kg of furosemide was injected intravenously, 3 times every 15 minutes, PRA and PNA were significantly increased with a concomitant increase in PAC. Sar1-Ile8-angiotensin II induced a significant increase in PAC and a slight increase in PRA, while no changes were found in PNA and the mean blood pressure. The increase in PNA induced by furosemide was inhibited dose-dependently by Sar1-Ile8-angiotensin II, through PRA and PAC were further increased. There results suggest that an administration of furosemide induced the increase in PNA and the increase in PNA by furosemide might by mediated by the renin-angiotensin system.

1-Sarcosine-8-Isoleucine Angiotensin II↗
PubMed1989

[Intra-arterial infusion chemotherapy with [Sar1, Ile8] angiotensin II in bladder cancer].

Twenty patients with bladder cancer were treated with intra-arterial infusion chemotherapy using CDDP and ADM in combination with [Sar1, Ile8] angiotensin II. A catheter was introduced into internal iliac artery by Seldinger's technique, and 100 mg of CDDP, 50 mg of ADM and 1 mg of [Sar1, Ile8] angiotensin II were infused through the catheter for 40 minutes. CR was observed in 8 of 20 patients. PR in 11 and NC in 1. Therefore, the response rate (CR + PR) was 95% (19/20). Side effects were generally mild and consisted of leukopenia, nausea, vomiting, diarrhea, alopecia, skin pigmentation and headache. Catheter-related complications were not observed. This study demonstrated that intra-arterial infusion chemotherapy with CDDP and ADM in combination with [Sar1, Ile8] angiotensin II was extremely effective in treating patients with bladder cancer.

1-Sarcosine-8-Isoleucine Angiotensin II↗
PubMed1994

Role of the NH2-terminal domain of angiotensin II (ANG II) and [Sar1]angiotensin II on conformation and activity. NMR evidence for aromatic ring clustering and peptide backbone folding compared with [des-1,2,3]angiotensin II.

The role of the NH2 termini of angiotensin II (ANG II) and [Sar1]ANG II on conformation and activity were examined by proton NMR two-dimensional-J-correlated spectroscopy and one-dimensional nuclear Overhauser effect studies in the relatively nonpolar "receptor-simulating" environment provided by dimethyl sulfoxide-d6, using the biologically inactive COOH-terminal pentapeptide [des1,2,3]ANG II as control. Irradiation of C alpha H, C2H, and C4H proton resonances in ANG II and [Sar1]ANG II resulted in enhancements of Tyr and Phe ring proton resonances, indicating that the three aromatic rings cluster together. Very strong enhancements (17-22%) of the C alpha Y proton resonance in ANG II and [Sar1]ANG II upon irradiation of the C alpha H proton resonance, and vice versa, revealed that a Tyr-Ile-His bend is a predominant feature of the conformation of the two agonists. In contrast, saturation of the C alpha H and C alpha Y proton resonances in the control pentapeptide [des-1,2,3]ANG II did not produce, respectively, any C alpha Y or C alpha H proton nuclear Overhauser effect enhancement, illustrating the absence of a Tyr-Ile-His bend in the truncated ANG II peptide. The present findings indicate that the NH2-terminal domain of ANG II appears to have an essential role in generating the biologically active charge relay conformation of the hormone.

Algorithms↗
PubMed1980

Sar1-Ile8-angiotensin II decreases urinary PGE2 and PGF2alpha excretion in rabbits on dietary sodium restriction.

Urinary PGE2 and PFG 2 alpha excretion (UPGV) were determined prior, during and after 48 h treatment with angiotensin-II-blocker, Sar1-Ile8-angiotensin II (200 microgram/kg/3 h), in rabbits maintained on chronic low (LS) or high (HS) salt diets. UPGE2V and F2 alpha were significantly (P < 0.001) higher in LS than in HS. Sar1-Ile-8-angiotensin II decreased the elevated UPGE2 V and UPGF2 alpha V in LS from 2.60 +/- 0.084 microgram/24 h to 1.13 +/- 0.21 microgram/24 h and from 6.63 +/- 0.61 to 3.77 +/- 0.86 microgram/24 h respectively. In animals with HS intake, angiotensin II blockade failed to effect urinary prostaglandin excretion.

1-Sarcosine-8-Isoleucine Angiotensin II↗
PubMed1993

Sar1-p-benzoylphenylalanine-angiotensin, a new photoaffinity probe for selective labeling of the type 2 angiotensin receptor.

Previous photoaffinity labeling of angiotensin II (Ang) receptors with azidophenylalanine containing Ang analogs produced high yield labeling of a 60 kDa protein on bovine adrenocortical membranes. This preparation is mostly enriched in the type 1 Ang receptor (AT1) and AT1 selective ligands (L158,809) totally prevented labeling, therefore confirming the AT1 nature of the labeled protein. Our attempt to photolabel the type 2 Ang receptor (AT2) of human myometrium with [Sar1,D-Phe(N3)8]Ang was unsuccessful, revealing a high degree of photolabeling selectivity. An Ang analog, [Sar1,Bpa8]Ang (or BpaAng) was prepared containing the photosensitive amino acid p-benzoylphenylalanine (Bpa). This compound was a specific but non-competitive Ang antagonist on rabbit aorta with a pA2 of 8.5. It displayed good binding affinities for bovine adrenocortical membranes (Kd = 6.5 nM), a predominantly AT1 preparation, and for human myometrium membranes (Kd = 0.39 nM), a predominantly AT2 preparation. Photolabeling experiments with iodinated BpaAng showed that AT1 was not covalently labeled whereas AT2 was covalently labeled with high yield. Labeling specificity was verified with the AT2-selective ligand PD123319 and with the AT1-selective antagonist L158,809. Our results indicate that 125I-BpaAng is exclusively labeling AT2 sites. This compound should be a useful tool for further biochemical characterization of the AT2 binding site.

Adrenal Cortex↗
PubMedDate not supplied

1H-NMR studies of [Sar1]angiotensin II conformation by nuclear Overhauser effect spectroscopy in the rotating frame (ROESY): clustering of the aromatic rings in dimethylsulfoxide.

The conformational properties of the octapeptide [Sar1]ANG II in dimethylsulfoxide-d6 were investigated by rotating frame nuclear Overhauser effect spectroscopy (ROESY). Interresidue ROESY interactions were observed between Tyr ortho and Phe ring protons, between Phe ring and Pro C gamma protons, and also between His C alpha and Pro C delta protons. A weak connectivity was also observed between the Sar N-CH3 protons and a Tyr ortho proton. Intraresidue interactions between alpha and beta protons in Tyr, His and Phe indicated restricted rotation for the side-chains of the three aromatic residues. These findings suggest that [Sar1]ANG II takes up a folded conformation in DMSO in which the three aromatic rings form a cluster. Connectivities between the His C alpha proton and the two Pro C delta protons illustrated a preferred conformation for angiotensin II in DMSO in which the His-Pro bond exists as the trans isomer. The NMR spectroscopic evidence is consistent with the presence of a Tyr charge relay system in the biologically active conformation of angiotensin II and with the postulated role of the Tyr hydroxyl group in angiotensin II for receptor activation.

Amino Acid Sequence↗
PubMed1994

Receptor binding radiotracers for the angiotensin II receptor: radioiodinated [Sar1, Ile8]Angiotensin II.

The potential for imaging the angiotensin II receptor was evaluated using the radioiodinated peptide antagonist [125I][Sar1, Ile8)angiotensin II. The radioligand provides a receptor-mediated signal in several tissues in rat (kidneys, adrenal and liver). The receptor-mediated signal of 3% ID/g kidney cortex should be sufficient to permit imaging, at least via SPECT. The radiotracer is sensitive to reductions in receptor concentration and can be used to define in vivo dose-occupancy curves of angiotensin II receptor ligands. Receptor-mediated images of [123I][Sar1, Ile8]angiotensin II were obtained in the rat kidney and Rhesus monkey liver.

1-Sarcosine-8-Isoleucine Angiotensin II↗
PubMed2004

The role of ADP-ribosylation factor and SAR1 in vesicular trafficking in plants.

Ras-like small GTP binding proteins regulate a wide variety of intracellular signalling and vesicular trafficking pathways in eukaryotic cells including plant cells. They share a common structure that operates as a molecular switch by cycling between active GTP-bound and inactive GDP-bound conformational states. The active GTP-bound state is regulated by guanine nucleotide exchange factors (GEF), which promote the exchange of GDP for GTP. The inactive GDP-bound state is promoted by GTPase-activating proteins (GAPs) which accelerate GTP hydrolysis by orders of magnitude. Two types of small GTP-binding proteins, ADP-ribosylation factor (Arf) and secretion-associated and Ras-related (Sar), are major regulators of vesicle biogenesis in intracellular traffic and are founding members of a growing family that also includes Arf-related proteins (Arp) and Arf-like (Arl) proteins. The most widely involved small GTPase in vesicular trafficking is probably Arf1, which not only controls assembly of COPI- and AP1, AP3, and AP4/clathrin-coated vesicles but also recruits other proteins to membranes, including some that may be components of further coats. Recent molecular, structural and biochemical studies have provided a wealth of detail of the interactions between Arf and the proteins that regulate its activity as well as providing clues for the types of effector molecules which are controlled by Arf. Sar1 functions as a molecular switch to control the assembly of protein coats (COPII) that direct vesicle budding from ER. The crystallographic analysis of Sar1 reveals a number of structurally unique features that dictate its function in COPII vesicle formation. In this review, I will summarize the current knowledge of Arf and Sar regulation in vesicular trafficking in mammalian and yeast cells and will highlight recent advances in identifying the elements involved in vesicle formation in plant cells. Additionally, I will briefly discuss the similarities and dissimilarities of vesicle traffic in plant, mammalian and yeast cells.

ADP-Ribosylation Factors↗
PubMed1975

Effect of angiotensin II and of an angiotensin II analogue (Sar1-Ile8-angiotensin II) on blood pressure, plasma aldosterone and plasma renin activity in the dog.

1. The effect of infusions of equimolar doses of angiotensin II (AII) and of the angiotensin analogue Sar1-Ile8-angiotensin II on arterial blood pressure, plasma aldosterone and plasma renin activity were compared in normal anaesthetized dexamethasone suppressed dogs. 2. Angiotensin II induced a significant increase of blood pressure and of plasma aldosterone whereas plasma renin activity decreased. The blood pressure was only slightly affected by large doses of the analogue. Plasma aldosterone, however, increased and plasma renin activity decreased. These changes were significant but less pronounced than after the infusions of angiotensin II. Plasma aldosterone remained high and renin activity low for 40 min after the infusions of the analogue. 3. The results suggest a strong agonistic potency of Sar1-Ile8-angiotensin II at the adrenal and renal angiotensin receptors, and that it is almost ineffective at the vascular receptors. The inhibition of renin secretion by angiotensin seems not be related to its vasoconstrictive activity.

Aldosterone↗
PubMed1979

Brain angiotensin II binding and central [Sar1,Ala8]angiotensin responses in normal rats and the New Zealand strain of genetically hypertensive rats.

1. Specific angiotensin II (ANGII) receptor binding was measured in regions of the brains of the New Zealand gentically hypertensive and normal rats. 2. ANGII receptor binding was consistently lower in the septum, midbrain, thalamus and posterior medulla of the genetically hypertensive rats than in normal rats. 3. Blood pressure responses to intraventricular injections of ANGII and an ANGII antagonist [Sar1,Ala8]angiotensin were studied in conscious and pentobarbitone-anaesthetized genetically hypertensive and normal rats. In conscious rats no significant difference between the two strains of rat was detected. 4. In pentobarbitone-anaesthetized rats intraventricular injection of 40 microgram of [Sar1,Ala8]angiotensin had a hypotensive effect which was three times greater in the genetically hypertensive rats than that observed in normal rats. The latency of this hypotensive effect was longer than the latency of the hypertensive effect of ANGII. 5. The drinking responses to intraventricular injections of ANGII were similar in genetically hypertensive and normal rats. 6. The physiological role of the ANGII system is discussed and it is concluded that an abnormality of this system in the brain may well be responsible for the hypertension found in the genetically hypertensive rat.

Angiotensin II↗
PubMed1996

Characterization of yeast sar1 temperature-sensitive mutants, which are defective in protein transport from the endoplasmic reticulum.

SAR1 encodes a low molecular weight GTPase that is essential in the early process of vesicular transport in the secretory pathway. By random and site-directed mutagenesis of the SAR1 gene, we have obtained three temperature-sensitive mutants, N132I, E112K, and D32G. They all show a defect in transport from the endoplasmic reticulum to the Golgi apparatus, and accumulate endoplasmic reticulum membranes at the restrictive temperature. This is consistent with our previous observations in vivo on a galactose-shutoff mutant as well as the in vitro results, and provides powerful tools for further genetic analyses.

Alleles↗
PubMed1998

Activities of mutant Sar1 proteins in guanine nucleotide binding, GTP hydrolysis, and cell-free transport from the endoplasmic reticulum to the Golgi apparatus.

Sar1p belongs to a unique subfamily of the small GTPase superfamily and is essential for the formation of vesicles that transport proteins from the endoplasmic reticulum to the Golgi apparatus. We have obtained mutants of the yeast SAR1 gene, which show several different phenotypes in cell growth and protein transport [Nakano, A. , Otsuka, H., Yamagishi, M., Yamamoto, E., Kimura, K., Nishikawa, S., and Oka, T. (1994) J. Biochem. 116, 243-247; Yamanushi, T., Hirata, A., Oka, T., and Nakano, A. (1996) ibid. 120, 452-458]. In this study, we have purified five mutant Sar1 proteins using an Escherichia coli expression system and characterized their biochemical properties in detail. Three of them prefer GDP binding to GTP binding and are thus regarded as GDP-form mutants, and one is insensitive to the GTPase-activating protein and is almost fixed in the GTP-bound state. The GDP mutants are defective in vesicle formation in vitro, whereas the GTP mutant can drive vesicle formation but not the overall transport to the Golgi. These mutants will be useful for further understanding of the regulation of the GTPase cycle of Sar1p.

Amino Acid Substitution↗
PubMed1994

Mutational analysis of the Sar1 protein, a small GTPase which is essential for vesicular transport from the endoplasmic reticulum.

SAR1 encodes a 21-kDa GTPase, which is required for vesicle formation from the endoplasmic reticulum in yeast. Although it belongs to the expanding small GTPase superfamily, there are interesting structural features that are unique to the Sar1 protein. We performed a site-directed mutational study to identify the amino acid residues that are essential for the Sar1p function. Among seven mutants we constructed, four are functionless by themselves, while two confer temperature sensitivity to cells. When the mutant proteins are overproduced in wild-type cells, all of these six show a dominant negative effect on cell growth. The replacement by serine of the only cysteine residue present in Sar1p caused no significant change in the growth phenotype. These findings are not only important for analyzing the mechanism of the Sar1p action in yeast, but will also be very useful for studying the function of Sar1p counterparts in higher eukaryotes.

Amino Acid Sequence↗
PubMed1992

Intraarterial infusion chemotherapy with [Sar1,Ile8]angiotensin II for bladder cancer.

Thirty-three patients with primary bladder cancer (nine stage T1 with multifocal tumors and 24 stage T2-4) were treated with intraarterial infusion chemotherapy including cisplatin, doxorubicin, and [Sar1,Ile8]Angiotensin II(AT II). Of the 32 evaluable patients, 12 had pathologically proven complete response (CR), 19 showed partial response (PR), and one showed no change (NC); the overall response rate (CR + PR) was 97%. The blood pressure increased in response to the administration of [Sar1,Ile8]AT II in all the patients; the mean increase in the systolic blood pressure was 36 mmHg. Most of the side effects were mild to moderate in severity, transient in nature, and included nausea/vomiting (100%), alopecia (84%), leukopenia (66%), headache (9%), nephrotoxicity (6%), diarrhea (3%), skin pigmentation (3%), and neurotoxicity (3%). One patient who dropped out of the study developed hemiplegia as a result of cerebral infarction. The findings indicate that it is necessary to exercise caution in selecting the patients to be subjected to this therapy. We conclude that intraarterial infusion chemotherapy combined with a vasoconstrictor has a significant effect not only against multifocal superficial bladder cancer but also against invasive bladder cancer.

1-Sarcosine-8-Isoleucine Angiotensin II↗
PubMed1988

Inability of [125I]Sar1, Ile8-angiotensin II to move between the blood and cerebrospinal fluid compartments.

The angiotensin II competitive antagonist [125I]-Sar1, Ile8-angiotensin II was not transported from the vascular space to the cerebroventricular space in either intact or nephrectomized rats. In addition [125I]Sar1, Ile8-angiotensin II lacked the capacity to move in the opposite direction over a 20-min collection period following cerebroventricular infusion. These data suggest that angiotensins lack the capacity to move freely between the blood and cerebrospinal fluid compartments and are consistent with the notion that blood-borne and cerebroventricular angiotensins access different receptor populations.

1-Sarcosine-8-Isoleucine Angiotensin II↗
PubMed1980

Constrasts and similarities of acute hemodynamic responses to specific antagonism of angiotensin II ([Sar1, Thr8] A II) and to inhibition of converting enzyme (captopril).

The early blood pressure and hemodynamic effects of the converting enzyme inhibitor (CEI), captopril, were compared in 23 hypertensive patients with those of a specific angiotensin II antagonist (AA), [Sar1, Thr8] A II. AA reduced mean arterial pressure (MAP) greater than 10 mm Hg only in seven of 23 patients vs 15 of 23 who responded to CEI (p less than 0.02). With both drugs, changes in MAP were not associated with significant changes in cardiac output (p greater than 0.10 for both drugs), but correlated with changes in systemic resistance (TPR); r = 0.84, p less than 0.001 for AA and r = 0.71, p less than 0.001 for CEI. Changes in TPR and MAP correlated significantly and inversely with log plasma renin activity in both instances; for AA, r = 0.829 and for CEI, r = -0.737; p less than 0.001 for both. The slopes of the two regression lines were not significantly different but the intercepts were +8.47 mm Hg for AA vs -10.17 mm Hg for CEI (p less than 0.001). This quantitative difference in response could be attributed either to an agonistic effect of [Sar1, Thr8] A II or to an additional vasodilator effect of captopril.

Adult↗